Isotretinoin (13-cis retinoic acid or 13-cis vitamin A), its isomers and some of its analogs are widely known to have therapeutic activity in the treatment of several severe skin disorders including cystic acne, hypertrophic lupus erythematosus, and keratinization disorders. Some evidence exists supporting the activity of isotretinoin in basal cell carcinoma and squamous cell carcinoma.
Unfortunately, isotretinoin is also a highly toxic drug. Indeed, although isotretinoin, which is a cis derivative, is known to be less toxic than all trans vitamin A derivatives, side effects resulting from its use such as headache, vomiting, irritation of mucosa and liver toxicity, occur frequently. Furthermore, isotretinoin is known to be highly teratogenic in both animals and humans.
In order to well understand the objectives and advantages of this invention, it is important to briefly summarize the physico-chemical pharmacokinetic properties of isotretinoin. Isotretinoin is a reddish-orange powder that is decomposed in the presence of light and atmospheric oxygen. Isotretinoin is poorly soluble in water, which results in its bioavailability being quite low after an oral intake (25% in fasted conditions and 40% in fed conditions). The maximum concentration (Cmax) is reached after 24 hours, while the (Cmax) of the active metabolite, 4-oxo-isotretinoin is reached after 6 hours. The elimination half-life of isotretinoin is of 7 to 37 hours while the half-life (t1/2) of the active metabolite is of 11 to 50 hours. The steady-state concentrations of isotretinoin are reached after 1 week of treatment.
Very few publications and/or patents about the pharmaceutical formulation of isotretinoin are available. The drug is available on most markets under the form of a soft gelatin capsule containing a fatty liquid formulation of isotretinoin.
U.S. Pat. No. 4,464,394 describes for the first time the therapeutic use of isotretinoin and also briefly describes compositions of isotretinoin. The compositions involve the use of an antioxidant agent and of a carrier like lactose, starches or polyethylene glycols.
EP 0184942 describes more specific compositions of isotretinoin involving the use of an antioxidant, a chelating agent, a pharmaceutical carrier and a suspending agent. The composition obtained is described as being stable over time.
U.S. Pat. No. 4,545,977 relates to improved compositions of isotretinoin wherein taurine is associated with isotretinoin to reduce the drug's side effects.
U.S. Pat. No. 5,716,928 describes a method for increasing bioavailability and for reducing inter and intra individual variability of an orally administered hydrophobic pharmaceutical compound. The method includes orally administering the pharmaceutical compound with an essential oil or essential oil component in an amount sufficient to provide greater bioavailability of the active ingredient.
U.S. Pat. No. 6,028,054 relates to a method for increasing bioavailability of an orally administered hydrophobic pharmaceutical compound to humans. The method includes orally administering the pharmaceutical compound concurrently with a bioenhancer comprising an inhibitor of an cytochrome P450 3A enzyme or an inhibitor of P-glycoprotein mediated membrane transport.
U.S. Pat. No. 5,993,858 describes a self-microemulsifying excipient formulation for increasing the bioavailability of a drug which includes an emulsion including an oil or other lipid material, a surfactant and an hydrophilic co-surfactant.
It is believed that the prior art does not disclose a composition of isotretinoin containing at least two lipid materials, one of them being hydrophilic. The said composition may be a suspension, emulsion or microemulsion.